SUMMARY Environmental tobacco smoke (ETS) or ?secondhand smoke? exposure leads to stress-induced adverse outcomes including cellular senescence and toxicological effects on the lungs associated with systemic response/injury and inflammation in airway and other organ disorders. Exosomes/microparticles play an important role in maintaining normal cellular homeostasis via intercellular communication. However, the characteristics and properties of exosomes from cells undergoing cellular senescence may be different, and they will have the potential to alter the phenotype of normal cells. Exosomes from mesenchymal stem cells (MSCs) may transfer molecular signatures encoded in encapsule from stem cells to senesced cells. Mitochondria quality control (mitophagy) is declined during aging and age-related degenerative processes, and in response to ETS and biomass smoke exposures in non-smokers). Our preliminary data show that exosomes differ from non-smokers vs smokers, and defective mitophagy is associated with cellular senescence in lung cells in response to ETS. No information is available on the restoration of cellular senescence and mitophagy by exosomes in lung cells exposed to ETS. In this exploratory (high risk and high impact) proposal, we hypothesize that exosomes are released from ETS exposed MSCs which alter normal lung cellular phenotypes in vitro and in vivo, and exosomes transfer from healthy MSCs rescue ETS-induced senescence phenotypes. We propose the following two specific aims to test the above hypothesis: Aim 1: Biochemical characterization and functional properties of MSCs-derived exosomes by ETS exposure, and their effects on lung cellular phenotypes in vitro. Aim 2: Functional properties of MSCs-derived exosomes and their effects on ETS-induced lung phenotypes in vivo. The proposed studies will have the potential to determine the characteristics and functional properties of exosomes from cells undergoing cellular senescence by ETS, which will have the potential to alter the phenotype of normal cells. The outcome will have translational potential as they will determine the mechanisms whereby possible attenuation of cellular senescence via exosome transfer from MSCs. Further, the outcome will be utilized to understand other inhaled oxidants/toxicants induced pulmonary and other systemic organ phenotypes and toxicological responses, and in chronic diseases for characterization of exosomes as biomarkers and therapeutic approaches.